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10/06/12

teriflunomide

Teriflunomide

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Teriflunomide
Systematic (IUPAC) name
(2Z)-2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]but-2-enamide
Clinical data
Pregnancy cat. Not yet classified
Legal status Investigational
Routes Oral
Pharmacokinetic data
Protein binding >99.3%
Half-life 2 weeks
Excretion Biliary/fecal, renal
Identifiers
CAS number 163451-81-8 
ATC code None
PubChem CID 5479847
ChemSpider 16737143 Yes
UNII 1C058IKG3B Yes
ChEMBL CHEMBL973 Yes
Chemical data
Formula C12H9F3N2O2 
Mol. mass 270.207 g/mol
SMILES eMolecules & PubChem
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Teriflunomide (also known as A77 1726) is the active metabolite of leflunomide.[1] Teriflunomide was investigated in the Phase III clinical trial TEMSO as a medication for multiple sclerosis (MS). The study was completed in July 2010.[2] 2-year results were positive.[3] However, the subsequent TENERE head-to-head superiority trial reported that "although permanent discontinuations [of therapy] were substantially less common among MS patients who received teriflunomide compared with interferon beta-1a, relapses were more common with teriflunomide."[4]

Contents

Mechanisms of action

Teriflunomide is an immunomodulatory drug inhibiting pyrimidine de novo synthesis by blocking the enzyme dihydroorotate dehydrogenase. It is uncertain whether this explains its effect on MS lesions.[5]
Teriflunomide inhibits rapidly dividing cells, including activated T cells, which are thought to drive the disease process in MS. Teriflunomide may decrease the risk of infections compared to chemotherapy-like drugs because of its more-limited effects on the immune system.[6]
It has been found that teriflunomid blocks the transcription factor NF-κB. It also inhibits tyrosine kinase enzymes, but only in high doses not clinically used.[7]

Activation of leflunomide to teriflunomide

Leflunomide.svg→E-Teriflunomide structure.svg↔Teriflunomide structure.svg
The structure which results from ring opening can interconvert between the E and Z enolic forms (and the corresponding keto-amide), with the Z enol being the most stable and therefore most predominant form.

Space filling model of the E isomer of teriflunomide

See also

See Leflunomide for information on pharmacokinetics, side-effects, contraindications and other data.

References

  1. ^ Magne D, Mézin F, Palmer G, Guerne PA (2006). "The active metabolite of leflunomide, A77 1726, increases proliferation of human synovial fibroblasts in presence of IL-1beta and TNF-alpha". Inflamm. Res. 55 (11): 469–75. DOI:10.1007/s00011-006-5196-x. PMID 17122964.
  2. ^ ClinicalTrials.gov Phase III Study of Teriflunomide in Reducing the Frequency of Relapses and Accumulation of Disability in Patients With Multiple Sclerosis (TEMSO)
  3. ^ "Sanofi-Aventis’ Teriflunomide Comes Up Trumps in Two-Year Phase III MS Trial". 15 Oct 2010.
  4. ^ Gever, John (June 4, 2012). "Teriflunomide Modest Help but Safe for MS". medpage. Retrieved June 04, 2012.
  5. ^ H. Spreitzer (March 13, 2006). "Neue Wirkstoffe - Teriflunomid" (in German). Österreichische Apothekerzeitung (6/2006).
  6. ^ Dr. Timothy Vollmer (May 28, 2009). "MS Therapies in the Pipeline: Teriflunomide" (in English). EMS News (May 28, 2009).
  7. ^ Breedveld, FC; Dayer, J-M (November 2000). "Leflunomide: mode of action in the treatment of rheumatoid arthritis". Ann Rheum Dis 59 (11): 841–849. DOI:10.1136/ard.59.11.841. PMC 1753034. PMID 11053058.


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